Solubility and dissolution rate issues still remain a challenge to the pharmaceutical scientists. These difficulties are more apparent with hydrophobic drugs, and with high number of hydrophobic drugs entering the drug discovery and product development pipeline, these issues become even more important to settle. Pharmaceutical actives belonging to Biopharmaceutics Classification System (BCS) class II and IV present solubility-related challenges in formulation development. Strategies for improving apparent solubility and dissolution rate include forming soluble salts for ionizable drugs, reducing crystal size, forming soluble pro-drugs, using amorphous forms, co-solvents and super disintegrants, and using surface active self-emulsifying systems.
With most sophisticated size reduction technologies being developed in recent years, size reduction to nanoparticles has attracted lot of attention in the formulation development of hydrophobic drugs. Nanoparticles can be generated by many means, like top-down approaches such as size reduction by advanced milling techniques or by bottom-up approaches like precipitation. However, due to small size and high surface area, the dispersion of the nanoparticles in the dissolution media often remains a challenge and requires addition of surface modifying agents to reduce the agglomeration tendency and increase the dispersability. A solid dispersion contains at least two components: a matrix and a pharmaceutical active ingredient. The matrix can be either amorphous or crystalline, and the drug can be dispersed within the matrix as an amorphous molecular dispersion or as amorphous particles or as nanosized crystals. Amorphous solid dispersion of insoluble pharmaceutical active in high molecular weight water-soluble polymeric matrices is reported to be highly efficient as it presents the pharmaceutical active at the molecular level to the dissolution media (U.S. Pat. No. 7,713,548). Amorphous solid dispersions are usually prepared by spray drying, by depositing drug solution onto the carrier in a fluidized bed granulator, by melt extrusion, by melt fusion, twin-screw extruder, evaporation, curing, microwaving, milling, ultra sound, spinning by mechanical admixture such as by ball milling and by mechanical admixture at an elevated but non-melting temperature.
Most common technique of generation of amorphous solid dispersion is solvent method that involves dissolution of the drug/pharmaceutical active and matrix material in a solvent. The solvent is then removed to leave a mixture of drug and matrix in solid form. Further solvent can be removed by vacuum drying, spray drying and freeze drying.
Commercialization of amorphous solid dispersion is still a challenge due to unpredictable physical stability of the amorphous pharmaceutical active (Critical Reviews™ in Therapeutic Drug Carrier Systems, 21(3):133-193 (2004)) and atypical dissolution behavior of amorphous dispersion dosage forms (Journal of Pharmaceutical Sciences 100(6): 2460-2468 (2011)). Problems with chemical stability due to interaction between drug-polymer matrixes also add to the complication. Phase separation due to external stresses during various manufacturing unit operations has to be monitored thoroughly for the success of amorphous solid dispersions. Most of the excipients used in the solid dispersions are polymeric in nature. Polymeric excipients result in drug being at least partially converted to amorphous form.
Latter has higher energy and undergoes recrystallization during shelf-life. Amorphous form also undergoes recrystallization during dissolution stage. It is hence difficult to predict the performance of the drug present in amorphous form. Dosage forms prepared using amorphous form also pose problems like recrystallization during processing, poor dispersability and retarded dissolution kinetics. Moreover, polymers generally are hygroscopic in nature and recent reports indicate this hygroscopic nature is detrimental to the stability of the amorphous solid dispersions, as moisture uptake by the polymers may lead to the phase separation which further may lead to physical instability of amorphous drug. Crystalline solid dispersions of the present invention, on other hand, offer advantage of higher dissolution rate compared to “raw” or “untreated” drug/pharmaceutical active.
Reference may be made to U.S. Pat. No. 5,456,923 discloses an invention comprising of employing a twin-screw extruder in the production of a solid dispersion. In accordance with the invention, a solid dispersion can be expediently produced without heating a drug and a polymer to or beyond their melting points and without using an organic solvent for dissolving both components.
In yet another reference U.S. Pat. No. 6,706,283 discloses an invention comprising of controlled release dosage forms for low solubility drugs, wherein an amorphous solid dispersion of the drug is coated with a non-dissolving and non-eroding coating that controls the influx of water to the core so as to cause extrusion of a portion of the core.
In another reference US 2009/0285905 discloses a pharmaceutical composition comprising of hydrophobic drug and hydrophilic components and spray drying them simultaneously in a spray dryer for uniform dry powder characteristics for inhalation drug delivery. The hydrophilic components used in the invention varied in their properties, which would affect the physical form of drug in the final product. The physical form of the drug in the final product, in the invention, is ill-defined.
WO 2010/133611 discloses an invention comprising of preparation of solid dispersion of drug with super disintegrant. The preparation comprises the steps of providing a crystalline drug in which the drug crystals have a median diameter U50% of not generally more than 20, preparing a dispersion or suspension of drug crystals in a disintegrant solution or suspension, and spray drying the dispersion or suspension to provide a solid crystalline drug dispersion.
U.S. Pat. No. 6,932,983 discloses an invention comprising of providing a low aqueous solubility drugs in a porous matrix form, preferably microparticles, to enhances dissolution of the drug in aqueous media
U.S. Pat. No. 4,721,709 discloses pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed onto carriers such as starch and/or microcrystalline cellulose. The rate of dissolution and absorption in the body is improved due to the very fine particle size of the drug adsorbed onto the carriers.
US 2009/0098200 discloses a pharmaceutical composition of hydrophobic drug interwoven with a polymeric matrix formed by two or more polymers, wherein one of the polymers is an amphiphilic polymer and the other polymer is either an amphiphilic polymer with a different hydrophobic-hydrophilic balance or a hydrophilic polymer, and the active hydrophobic drug has modified physicochemical properties. The composition forms colloidal nanodispersion upon contact with aqueous media. The hydrophobic drug is either in crystalline or amorphous form in the final product. However, the presence of amorphous hydrophobic drug could cause physical instability during the shelf-life. Presence of amorphous form of hydrophobic drug in the final product would also induce interactions with polymers which may lead to chemical instability.
US 2007/0134340 discloses an invention which provides the process of preparation of nanocrystals or polymer doped nanocrystals of hydrophobic drug molecules as stably dispersed in an aqueous system which are prepared without stabilizers like surfactants and the like. Drug efficacy of these nanocrystals was found to be comparable with that of same drug formulated in conventional delivery vehicles under in vitro and in vivo conditions.
In WO/1997/013503 a method of synthesizing nanoparticles composites by combining an agent and a matrix to form a composite mixture in an organic solvent or solvent/water is disclosed further mixture was spray dried to remove the solvent. Here the matrix used is mannitol. Type of matrix material, spray drying conditions and properties of the agent determine the solid form being formed.
In yet another reference U.S. Pat. No. 5,976,574 method for preparing dry powders having hydrophobic and hydrophilic components is disclosed. The process comprises combining solutions or suspensions of the components and spray drying them simultaneously in a spray drier. The hydrophobic component may be dissolved in an organic solvent and the hydrophilic component suspended therein wherein the hydrophilic component used is mannitol. This prior art mentions use of solubilizing the hydrophobic drug in a solvent and suspending the hydrophilic excipient in the solution. The resultant dispersion is spray dried to obtain coating of hydrophilic particles with hydrophobic drug. The method relies on separation of submicron particles by using separation techniques like cyclone separator. In compare, present invention uses a solution of the active agent and matrix forming agent wherein the latter acts as a crystallization inducer for the active agent. Crystallization during spray drying happens to achieve nanocrystalline state of active agent in the matrix of the crystallization inducing excipient.
In yet another reference U.S. Pat. No. 5,985,248 preparation of dry powder compositions is disclosed. In particular, spray drying method which permits simultaneous spray drying of the hydrophobic component with a hydrophilic component, such as a hydrophilic pharmaceutical excipient, under conditions which result in a dry powder comprising mixtures of both the hydrophilic and hydrophobic components. This prior art document discloses use of solution of hydrophobic agent and hydrophilic agent in a common solvent/solvent system. The resultant solution is spray dried to achieve individual particles in the submicron range. The spray dried product is further broken down into smaller particles using appropriate de-agglomeration tools like size screening. Thus, prior art in no way enables present invention wherein essentially nanocrystalline active is produced due to use of crystallization inducing excipient during the spray drying process.
In yet another reference WO/2007/136830 a process for producing particles comprising, preparing a solution of a compound with at least one solvent; spraying the solution into a chamber under conditions that allow for a substantial amount of the solvent to be removed from said solution, such that particles of said compound have a mean diameter of less than or equal to 3000 nm. This prior art describes spray drying of API solution to obtain particles of pure API. This is not relevant to our invention, as it deals with generation of nanocrystalline solid dispersion in presence of crystallization inducing excipient.
In review article titled “A review on drug nanocrystal a carrier free drug delivery” by; Patel Anita P; various methods for the production of drug nanocrystals are disclosed like a method wherein drug nanosuspensions are spray dried, and the nanosuspensions are formed by mixing drug with sugar alcohols like mannitol. This article describes details about nanocrystals present in suspended form in a solvent system. It also mentions carrier free drug delivery system in suspension, whereas present invention mentions preparation of nanocrystals in dry form along with a carrier such as mannitol.
Another reference titled “Nanoparticle Formulation for Hydrophilic & Hydrophobic Drugs” by Vivek Kumar Gupta discloses the production of nano particles of drug, by spray drying in the presence of sugar excipients such as lactose and mannitol. This document talks about preparation of nano particulate drug delivery system formed an intact structure of polymers with API distributed in it. Polymeric matrix forming agents usually form amorphous solid dispersions, as they impede crystallization of active, by decreasing molecular mobility, by virtue of their high viscosity. In comparison, present invention deals with use of crystallization inducing agent to produce nanocrystalline solid dispersion.
Thus the above references do not enable formation of nanocrystalline solid dispersion whereas present invention relates to formation of nanocrystalline solid dispersion, by inclusion of crystallization inducing excipient.
Existing drawbacks in available art, like multi-step process for the preparation and ill-defined physical form etc. that affect the biopharmaceutical properties during their shelf-life have been overcome by the present invention.